Cytochrome P450 monooxygenases oxidation

Figure 17.7 Reaction sequence for oxidation of an organic substrate, RH, by a cytochrome-P450 monooxygenase (after Ullrich, 1972, Schlichting et al., 2000).

Oxidation, demethylation, and other alterations are catalyzed by one or more of the nearly 300 cytochrome P450 monooxygenases present in the liver (step c). Oxidation products may be detoxified by glutathione S-transferases, step d (see also Box ll-B).b,c,cc... 

Whereas most, if not all, of the enzymes involved in xenobiotic metabolism can form reactive metabolites (Table 8.1), the enzyme systems most frequently involved in the activation of xenobiotics are those which catalyze oxidation reactions. The cytochrome P450 monooxygenases (CYP) are by far the most important enzymes involved in the oxidation of xenobiotics. This is because of the abundance of CYP (especially in the liver), the numerous isozymes of CYP, and the ability of CYP to be induced by xenobiotic compounds. 

Oxidation Cytochrome P450s Prostaglandin synthetase Flavin-containing monooxygenases Alcohol and aldehyde dehydrogenases... 

The induction of liver enzymes has been demonstrated in many species, including humans, and probably represents a homeostatic, defense mechanism. Induction usually requires multiple exposures to the inducing agent over a period of several days, the time required for the synthesis of new protein. Enzymes induced include the cytochrome P450 monooxygenase system glucuronyltransferase the microsomal ethanol oxidative system and the steroid-metabolizing system. 

Similarly, for tertiary amines a distinction can be made between oxometal and peroxometal pathways. Cytochrome P450 monooxygenases catalyze the oxidative N-demethylation of amines in which the active oxidant is a high-valent oxoiron species. This reaction can be mimicked with some oxometal complexes (Ruv=0), while oxidation via peroxometal complexes results in oxidation of the N atom (Fig. 4.93 a and b) [261]. A combination of MTO/hydrogen peroxide can... 

Organophosphate insecticides with the P=S group are oxidatively desulfurated by cytochrome P450 monooxygenases of insects to their corresponding P=0 analogs. This reaction results in activation (increased toxicity), because the product, P=0, binds more tightly to the acetylcholinesterase than the parent compound and, thus, to more potent acetylcholinesterase inhibitors. For example, parathion is oxidatively desulfurated to paraoxon. 

Some insecticides are known to affect the process of oxidative phosphorylation (Figure 7.27). Sulfluramid is first N-deethylated by cytochrome P450 monooxygenases to become perfluorooctane sulfonamide in vivo (Figure 7.28). This oxidative metabolite acts... 

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